OVEREXPRESSION OF A CALCIUM-BINDING PROTEIN, S100-BETA, IN ASTROCYTESALTERS SYNAPTIC PLASTICITY AND IMPAIRS SPATIAL-LEARNING IN TRANSGENICMICE

Recent evidence suggests that slowly propagating Ca2+ waves from astro cytes can modulate the function of neurons. Altering astrocytic calciu m processes in vivo may therefore affect neuronal and behavioral pheno types. Previously, we generated transgenic mice that overexpress an as trocytic calcium-binding protein, S100 beta. Immunocytochemistry and i n situ hybridization showed elevated expression in the astrocytes of t he hippocampus and other brain regions. Neurons in the hippocampus wer e negative for S100 beta. In this paper we analyze the hippocampal ele ctrophysiology and learning properties of mice from two transgenic lin es. Significant differences were found between the hippocampal slices of normal and transgenic mice in their response to high frequency (100 Hz) stimulation. The overall distribution of post-tetanic excitatory postsynaptic potentials (EPSP) of the slices from the transgenic mice was shifted significantly toward smaller values to a degree that 25% o f slices exhibited depression. The altered hippocampal neurophysiology was accompanied by an impairment in a hippocampal-dependent learning task. Transgenic mice showed significant impairment in a spatial versi on of the Morris water maze, however, they performed normally in non-s patial tasks. Probe trials showed that transgenic mice, though signifi cantly impaired, also acquired spatial information. The results sugges ted that the impairment was not due to motor dysfunction, impaired vis ion or motivation of the transgenic mice, findings compatible with a p ossible hippocampal mechanism. We conclude that overexpression of S100 beta in astrocytes impairs, but does not abolish, the ability to solv e a spatial task, and it leads to significantly decreased post-tetanic potentiation in the hippocampal slice. We hypothesize that the change s are due to calcium mediated processes. Our results support the notio n that astrocytes are involved in higher brain functions.